Loss of PTEN expression is associated with increased biologic potential of aggressive behavior in prostate cancer. Both the IGF-1 axis and PTEN act on the PI3K/Akt signaling pathway, and activation of this pathway enhances prostate carcinogenesis through a variety of mechanisms, including increasing proliferation. One target of this signaling pathway is the cyclin-dependent kinase inhibitor p27. Loss of p27 expression is associated with poor prognosis in prostate cancer. Our goal is to extend our current understanding of prostate cancer to specific molecular alterations that determine biologic potential. Thus, to complement the extensive clinical, serological and nutritional database we already assembled within the Physicians' Health Study, we propose to obtain and archive paraffin-embedded prostate cancer tissue blocks from 828 cases of prostate cancer from 1982 to 2002. In this project, we will assess standard histopathology, PTEN and p27 expression, and proliferation. We will examine whether the prevalence of loss of PTEN and p27 expression in prostate cancers is decreased in cancers detected through PSA screening, and we will compare the prevalence of loss of PTEN and p27 in tumors from African-American men and Caucasian men. We will also examine whether loss of PTEN expression is related to loss of p27 expression, increased proliferation, and worse prognosis (mortality, and PSA relapse) in prostate cancer, and whether loss of p27 expression is related to increased proliferation, and worse prognosis. Using our serological samples, we will examine whether high level of plasma IGF-1 and low level of IGFBP-3 are related to decreased p27 expression, and increased proliferation in prostate cancer. Finally, we will examine whether markers of prostate cancer progression (loss of p27 expression, and increased proliferation) are increased, and prognosis worsened, by high level of plasma IGF-1 and low level of IGFBP-3 primarily in tumors without loss of PTEN expression. The tumor markers we plan to assess in this project, as well as future novel markers discovered through other SPORE projects, will provide the basis for future studies of prognostic indicators.